1. Field of the Invention
The present invention relates generally to the fields of neurobiology, endocrinology, and psychiatry. More specifically, the present invention relates to the study of anxiety and auditory function in mice deficient for the urocortin gene.
2. Description of the Related Art
Neuropeptides are ubiquitous throughout the central and peripheral nervous systems, and play both primary transmitter and modulatory roles in biology. In the nervous system, neuropeptides play important roles in nociception, feeding behavior and stress response.
A series of peptides known as the urocortin (Ucn) peptides, including urocortin, urocortin II, and urocortin III (6-8) or as stresscopin and stresscopin-related peptide (9) have been cloned. Urocortin is very similar in structure to corticotropin releasing factor (CRF), first identified from the mammalian brain (1), which has been shown to be important in regulating the hypothalamic-pituitary-adrenal (HPA) axis and to play a prominent role in stress related responses (2). Various other non-mammalian peptides, also structurally similar to CRF have also been cloned (3-5), including fish urotensin I, and amphibian sauvagine. Additionally, urocortins, like CRF, exert their bioactivities via activating CRF receptors 1 and 2 (CRF1 and CRF2) (6), but urocortin has an approximately 40 fold higher affinity for CRFR2 and about 6 fold higher affinity for CRFR1 than CRF (6). Therefore, it has been postulated that urocortin may be an endogenous ligand for CRFR2.
A complete understanding of the full role for the urocortins has remained elusive while the roles for CRF are relatively well known. An examination of urocortin expression patterns and the administration of urocortin peptides into animals followed by the measurement of physiological responses gave insight into the role of urocortin in stress related response behaviors. High expression of urocortin is found in the Edinger-Westphal nucleus, the lateral superior olive (LSO), and the supraoptic nuclei (10). Urocortin neuronal fibers are found throughout the brain including the lateral septum in the forebrain, several motor nuclei in the brainstem, the olivocochlear fiber pathway, and in the spinal cord (10).
Central administration of urocortin has been shown to induce a variety of effects including suppression of food intake (11) and modulation of gastric motility (12). As CRFR2 is localized to the ventral medial hypothalamus, a central site of food intake regulation and satiety, it is possible that urocortin acts on these receptors to affect feeding.
A central injection of urocortin can also induce behavioral consequences such as increased locomotion and anxiety (13, 14), suggesting that urocortin, similar to CRF, is an anxiogenic agent in the brain. However, since urocortin can bind and activate both CRF receptor subtypes, administered urocortin might non-selectively activate receptors in areas where endogenous urocortin may not be present.
Urocortin has also been indicated in auditory physiology. The central nervous system exerts unique control over the auditory system that is not found in any other mammalian sensory system. By means of descending efferent fibers, cell bodies located in the superior olivary complex synapse directly with the hair cells of the organ of Corti, as well as with spiral ganglion cell dendrites located immediately adjacent to the inner hair cells. The classical anatomy of the olivocochlear system has been understood for many years (15).
In general, there are two main divisions of the olivocochlear system, identified as the lateral and the medial olivocochlear system. In rodents, the lateral system may be broken down into two systems itself, namely, those cells that lie within the boundaries of the lateral superior olive, and those that lie along its margins(16). The medial olivocochlear system synapses directly with the outer hair cells, while the lateral system synapses almost exclusively with elements within the inner hair cell region, including the inner hair cells themselves (17, 18) ) and the radial dendrites of the spiral ganglion neurons(18). Such direct innervation to inner hair cells is abundant in the developing cochlea but relatively scant in adults.
There is some immunocytochemical evidence that the lateral olivocochlear system also synapses with the outer hair cells (19). Immunocytochemical data indicate that the medial olivocochlear system is purely cholinergic (19). However, the lateral olivocochlear system is neurochemically heterogeneous, and the expression of classical neurotransmitters such as gamma aminobutyric acid (GABA) and acetylcholine (ACh) is spatially segregated within the LSO(19). Cholinergic lateral olivocochlear neurons also express a number of peptides that have been proposed to act as neuromodulators (19-24). Despite the numerous peptides expressed in the olivocochlear system, the roles they play in hearing has remained unclear, although roles for calcitonin gen-related peptide (CGRP) at the cellular level have been demonstrated in amphibian lateral line (25-27).
The prior art is lacking in information regarding the physiological roles of urocortin in auditory function and stress-related behaviors and also in null mutant mice deficient for urocortin to study such roles. The present invention fulfills this longstanding need and desire in the art.